Dosage form comprising liquid formulation

ABSTRACT

A dosage form is disclosed comprising a drug formulation that self-emulsifies in said dosage form.

REFERENCE TO RELATED APPLICATION

This application claims the benefits of provisional application SerialNo. 60/099,619 filed Sep. 9, 1998.

FIELD OF THE INVENTION

The present invention pertains to a dosage form comprising a liquidformulation comprising a drug. More particularly, the invention concernsa dosage form comprising a liquid formulation comprising a drug that canself-emulsify to enhance the solubility, the dissolution, and thebioavailability of the drug. The invention concerns also a method ofenhancing the therapeutic effect of a drug by using the dosage form ofthe invention

BACKGROUND OF THE INVENTION

Many drugs administered by the drug dispensing art possess hydrophobicproperties that diminish their bioavailability caused by the slow rateof dissolution and concomitantly diminish their therapeutic effect. Thisis a serious problem with hydrophobic drugs. For example, thepreparation and use of stable aqueous formulations comprising ahydrophobic drug, such as insoluble steroids including cortisoneacetate, progesterone, testosterone propionate, estradiol monobenzoate,and the like hydrophobic drugs often leads to unwanted problems. Theseproblems are exemplified by the growth of large crystals that can (1)diminish solubility, dissolution, and bioavailability of a drug; (2) bea source of irritation to a patient; and (3) give rise to mechanicaldifficulties in attempting to pass large crystals through hypodermicneedles and through enteral and parenteral tubes.

It will be appreciated by those versed in the drug dispensing arts thatif a dosage form comprising a drug formulation is made available thatovercomes the tribulations of the prior art, such a dosage form wouldhave a positive value in the drug dispensing art. Likewise, it will bescientifically self-evident to those versed in the drug delivery art,that if a dosage form is made available that delivers the essentiallyprescribed dose, such a dosage form would have immediate acceptance inthe fields of human and veterinary medicine.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide a dosage form for the sustainedrelease and the controlled delivery of a beneficial drug that overcomesthe shortcomings associated with the prior art.

Another object of the invention is to provide a dosage form comprising aliquid formulation comprising a drug that can be delivered in apreselected and prescribed does of drug to a patient in need of therapy.

Another object of the invention is to provide a liquid formulationcontaining an aqueous insoluble drug that can now be dispensed in aknown dose for a therapeutic use.

Another object of the invention is to provide a dosage form comprising aliquid formulation that undergoes conversion to an in situ,self-emulsifying formulation to enhance the oral bioavailability of adrug.

Another object of the invention is to provide a stable emulsioncomprising an aqueous insoluble drug that remains relatively free ofcrystal growth, even after extended periods of time.

Another object of the invention is to provide a liquid formulation thatcan self-emulsify in sit to an oil-in-water microemulsion and therebyessentially prevent drug particles from aggregation/agglomeration duringstorage and drug delivery over time.

Another object of the invention is to provide an oil-in-watermicroemulsion wherein a drug has a higher solubility than in water.

Another object of the invention is to provide a self-emulsifying liquidcarrier that enhances bioavailability in vivo of poorly absorbed drugsand is compatible with osmotic dosage forms.

Another object of the invention is to provide a dosage form fordelivering in vivo a beneficial drug that is difficult to deliver andnow can be delivered by this invention in a therapeutically effectivedose over twenty-four hours.

Another object of the invention is to provide a dosage form comprising acapsule coated with a semipermeable that comprises a drug in amicroemulsion formulation.

Another object of the invention is to provide an injection-molded dosageform comprising a hydrophobic drug in a microemulsion for delivery at aknown rate over a sustained release period.

Other objects, features, aspects and advantages of this invention willbe more apparent to those versed in the drug delivery art from thefollowing detailed specification taken in conjunction with the drawingsand the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawing figures, which are not drawn to scale but are set forth toillustrate embodiments of the invention, are as follows:

Drawing FIG. 1 is a closed, general view of a dosage form provided bythe invention;

Drawing FIG. 2 is an opened view of the dosage form of drawing FIG. 1,wherein the dosage from comprises a capsule made of two parts consistingof a body portion and a cap portion, which capsule contains a drugemulsion formulation and an expandable composition;

Drawing FIG. 3 is an opened view of the dosage form of drawing FIG. 1,wherein the dosage form comprises a capsule made of a single piece andcontains a drug emulsion formulation and an expandable composition;

Drawing FIG. 4 is an opened view of the dosage form of drawing FIG. 1,formed by injection-molding as a single piece and comprises a drugemulsion formulation and an expandable composition;

Drawing FIGS. 5A and 5B depict release rate and the cumulative amountreleased from a dosage form;

Drawing FIG. 6 depicts the cumulative dose released over time;

Drawing FIG. 7 depicts the cumulative dose released over time;

Drawing FIG. 8 depicts particle size in a formulation provided by theinvention;

Drawing FIG. 9 depicts the solubility of progesterone in components ofthe invention;

Drawing FIG. 10 depicts progesterone solubility in self-emulsifiedliquid carriers; and

Drawing FIGS. 11 to 15 depict the results of pharmacokinetic studiesusing the dosage forms of the invention

In the drawings, and in the specification, like parts in related figuresare identified by like numbers. The terms appearing earlier in thespecification are defined later in the specification.

DETAILED DESCRIPTION OF THE INVENTION AND DRAWINGS

The term emulsion as used in this specification denotes a two-phasesystem in which one phase is finely dispersed in the other phase. Theterm emulsifier, as used by this invention, denotes an agent that canreduce and/or eliminate the surface and the interfacial tension in atwo-phase system. The emulsifier agent, as used herein, denotes an agentpossessing both hydrophilic and lipophilic groups in the emulsifieragent. The term microemulsion, as used herein, denotes a multicomponentsystem that exhibits a homogenous single phase in which quantities of adrug can be solubilized. Typically, a microemulsion can be recognizedand distinguished from ordinary emulsions in that the microemulsion ismore stable and usually substantially transparent. The term solution, asused herein, indicates a chemically and physically homogenous mixture oftwo or more substances. The term solubility, as used herein, denotes asolid brought into contact with a liquid, whereby molecules of the solidestablish an equilibrium with the liquid leaving the solid and returningto it. The term slightly soluble, as used herein, denotes 100 to 1,000parts of solvent for 1 part of solute, very slightly soluble from 1,000to 10,000 parts of solvent for 1 part of solute, and practicallyinsoluble, or insoluble denotes more than 10,000 parts of solvent to 1part of solvent. The term dissolution denotes a process by which a solidsolute enters into solution. The term bioavailability indicates theamount of drug that reaches the general blood circulation from anadministered dosage form.

Turning now to the drawings in detail, which drawings are examples ofvarious dosage forms provided by the invention, and which examples arenot to be construed as limiting, one example of a dosage form is seen indrawing FIG. 1. In drawing FIG. 1, a dosage form 10 is seen in closedview comprising a body member 11, comprising a wall 12 that surrounds aninternal compartment or space, not shown. Dosage form 10 comprises alead end 9 with an orifice 13 and a bottom end 8.

In drawing FIG. 2, dosage form 10 comprises body member 11 comprising awall 12 that surrounds and forms an internal compartment or space 14.Wall 12 comprises an orifice 13 that communicates with the internalcompartment 14. A capsule 15 is enclosed in internal compartment 14.Capsule 15 is comprised of two parts, a cap 16 and a receiving body 17,which are fitted together after the larger body portion is filled firstwith a drug emulsion formulation 19 and then a push displacement layer18.

Capsule 15 is composed of two sections that are fitted together byslipping or telescoping the cap section over the body section, thuscompletely surrounding and encapsulating the emulsion formulation. Hardcapsules are made by dipping stainless steel molds into a bathcontaining a solution of a capsule lamina-forming material to coat themold with the material. Then, the molds are withdrawn, cooled, and driedin a current of air. The capsule is stripped from the mold and trimmedto yield a lamina member with an internal lumen. The engaging cap thattelescopically caps the formulation receiving body is made in a similarmanner. Then, the closed and filled capsule is capsuled with asemipermeable lamina. The semipermeable lamina can be applied to capsuleparts before or after parts and are joined into the final capsule. Inanother embodiment, the hard capsules can be made with each part havingmatched locking rings near their opened end that permit joining andlocking together the overlapping cap and body after filling withformulation. In this embodiment, a pair of matched locking rings areformed into the cap portion and the body portion, and these ringsprovide the locking means for securely holding together the capsule. Thecapsule can be manually filled with the formulation, or they can bemachine filled with the formulation. In the final manufacture, the hardcapsule is capsuled with a semipermeable lamina permeable to the passageof fluid and substantially impermeable to the passage of useful agent asdescribed hereafter.

Capsule 15, distant from orifice 13, contains an expandable composition18, initially in contact with the end of capsule 15. Expandablecomposition 18 is a push-driving force that acts in cooperation withdosage form 10 and capsule 15 for delivering a drug 20 emulsionformulation 19 from dosage 10. Composition 18 exhibits fluid imbibingand/or absorbing properties. Composition 18 comprises a hydrophilicpolymer that can interact with water and aqueous biological fluids andthen swell or expand. The hydrophilic polymers are known also asosmopolymers, osmogels, and hydrogels, and they exhibit a concentrationgradient across wall 12, whereby they imbibe fluid into dosage form 10.Representative of hydrophilic polymers are poly(alkylene oxide) of1,000,000 to 10,000,000 weight average molecular weight includingpoly(ethylene oxide), and an alkali carboxymethylcellulose of 10,000 to6,000,000 weight average molecular weight including sodiumcarboxymethylcellulose. Composition 18 may comprise 10 mg to 425 mg ofosmopolymer. Composition 18 comprises 1 to 50 mg of a poly(cellulose) ofa member selected from the group consisting of hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, andhydroxypropylbutylcellulose. Composition 18 comprises 0.5 mg to 75 mg ofan osmotically effective solute, known also as osmotic solute andosmagent, that imbibe fluid through wall 12 into dosage form 10. Theosmotically effective solutes are selected from the group consisting ofa salt, acid, amine, ester and carbohydrate selected from the groupconsisting of magnesium sulfate, magnesium chloride, potassium sulfate,sodium sulfate, lithium sulfate, potassium acid phosphate, mannitol,urea, inositol, magnesium succinate, tartaric acid, sodium chloride,potassium chloride, and carbohydrates such as raffinose, sucrose,glucose, lactose, and sorbitol. Composition 18 optionally comprise 0 wt% to 3.5 wt % of a colorant, such as ferric oxide. The total weight ofall components in composition 18 is equal to 100 wt %.

The emulsion formulation comprises 100 mg to 1500 mg, or 0.5 wt % to 65wt % of a drug 20. Representative drugs include a progestin or anestrogen such as a progestogenic steroid selected from the groupconsisting of progesterone, norethindrone, levonorgestrel, norgestimate,northindrone, and 17-hydroxyprogesterone; an estrogenic steroid selectedfrom the group consisting of estradiol, estradiol valerate, estradiolbenzoate, ethinyl estradiol, estrone, estrone acetate, estriol, andestriol triacetate; representative of additional drugs that are veryslightly soluble or practically insoluble in water that can be deliveredby the dosage form of this invention comprises diphenidol, meclizine,prochloperazine maleate, anisidione, diphenadione, erythrityltetranitrate, dizoxin, isoflurophate, reserpine, acetazolamide,methazolamide, bendroflumethiazide, clorpropamide, tolazamide,phenaglycodol, allopurinol, aluminum aspirin, metholrexate, acetylsulfisoxazole, enitabas, flutamide, cyclosporine, risperidone,fluniside, budesonide, lovastatin, simvastatin, etopside, triamcinolone,famotidine, cisapride, and erythromycin.

The invention is operable for the delivery also of pharmacologicallyactive peptides, protein anabolic hormones, growth promoting hormones,endocrine system hormones, procine growth hormones, bovine growthpromoting hormone, equine growth promoting hormone, ovine growthpromoting hormone, human growth promoting hormone, hormones derived fromthe pituitary and hypothalmus glands, recombinant DNA, somatropin,somatotropin, gonadotropic releasing hormone, follicle stimulatinghormone, luteinizing hormone, LH-RH, insulin, colchicine, chlorionicgonadotropin, oxytocin, vasopressin, desmopressin, adrenocorticotrophichormone, prolactin, cosyntropin, bypressin, thyroid stimulating hormone,secretin, pancreozymin, enkephalin, glucagon, and like drugs. The drugsare known to the medical art in U.S. Pat. No. 4,111,201 issued toTheeuwes and in U.S. Pat. No. 4,957,494 issued to Wong, Theeuwes andEckenhoff.

The emulsion formulation comprises 0.5 wt % to 99 wt % of a surfactant.The surfactant functions to prevent aggregation, reduce interfacialtension between constituents, enhance the free-flow of constituents, andlessen the incidence of constituent retention in the dosage form. Thetherapeutic emulsion formulation of this invention comprises asurfactant that imparts emulsification comprising a member selected fromthe group consisting of polyoxyethylenated castor oil comprising 9 molesof ethylene oxide, polyoxyethylenated castor oil comprising 15 moles ofethylene oxide, polyoxyethylene caster oil comprising 20 moles ofethylene oxide, polyoxyethylenated caster oil comprising 25 moles ofethylene oxide, polyoxyethylenated caster oil comprising 40 moles ofethylene oxide, polyoxyethylenated castor oil comprising 52 moles ofethylene oxide, polyoxyethylenated sorbitan monopalmitate comprising 20moles of ethylene oxide, polyoxyethylenated sorbitan monostearatecomprising 20 moles of ethylene oxide, polyoxyethylenated sorbitanmonostearate comprising 4 moles of ethylene oxide, polyoxyethylenatedsorbitan tristearate comprising 20 moles of ethylene oxide,polyoxyethylenated sorbitan monostearate comprising 20 moles of ethyleneoxide, polyoxyethylenated sorbitan trioleate comprising 20 moles ofethylene oxide, polyoxyethylene lauryl ether, polyoxyethylenated stearicacid comprising 40 moles of ethylene oxide, polyoxyethylenated stearicacid comprising 50 moles of ethylene oxide, polyoxyethylenated stearylalcohol comprising 2 moles of ethylene oxide, and polyoxyethylenatedoleyl alcohol comprising 2 moles of ethylene oxide. The surfactants areavailable from Atlas Chemical Industries, Wilmington, Del.; DrewChemical Corp., Boonton, N.J.; and GAF Corp., New York, N.Y.

The drug emulsified formulation of the invention initially comprises anoil phase. The oil phase of the emulsion comprises any pharmaceuticallyacceptable oil which is not invisible with water. The oil can be anedible liquid such as a non-polar ester of an unsaturated fatty acid,derivatives of such esters, or mixtures of such esters can be utilizedfor this purpose. The oil can be vegetable, mineral, animal or marine inorigin. Examples of non-toxic oils comprise a member selected form thegroup consisting of peanut oil, cottonseed oil, sesame oil, olive oil,corn oil, almond oil, mineral oil, castor oil, coconut oil, palm oil,cocoa butter, safflower, a mixture of mono- and diglycerides of 16 to 18carbon atoms, unsaturated fatty acids, fractionated triglyceridesderived from coconut oil, fractionated liquid triglycerides derived fromshort chain 10 to 15 carbon atoms fatty acids, acetylatedmonoglycerides, acetylated diglycerides, acetylated triglycerides, oleinknown also as glyceral trioleate, palmitin known as glyceryltripalmitate, stearin known also as glyceryl tristearate, lauric acidhexylester, oleic acid oleylester, glycolyzed ethoxylated glycerides ofnatural oils, branched fatty acids with 13 molecules of ethyleneoxide,and oleic acid decylester. The concentration of oil, or oil derivativein the emulsion formulation is 1 wt % to 40 wt %, with the wt % of allconstituents in the emulsion preparation equal to 100 wt %. The oils aredisclosed in Pharmaceutical Sciences by Remington, 17^(th) Ed., pp.403-405, (1985) published by Mark Publishing Co., in Encyclopedia ofChemistry, by Van Nostrand Reinhold, 4^(th) Ed., pp. 644-645, (1984)published by Van Nostrand Reinhold Co.; and in U.S. Pat. No. 4,259,323issued to Ranucci.

Capsule 15, as seen in drawing FIG. 2, is surrounded by a wall 12. Wall12 comprises a composition permeable to the passage of fluid, aqueousand biological fluid present in the environment of use, in animalincluding a human, and wall 12 is substantially impermeable to thepassage of drug 20, and the components of emulsion formulation 19. Wall12 is a non-toxic and it maintains its physical and chemical integrityduring the drug delivery device of dosage form 10. Representative ofmaterials for forming wall 12, include semipermeable polymers,semipermeable homopolymers, semipermeable copolymers, and semipermeableterpolymers. The polymers comprising wall 12 include cellulose esters,cellulose ethers, and cellulose ester-ethers. These cellulosic polymershave a degree of substitution, D.S., on their anhydroglucose unit fromgreater than 0 up to 3 inclusive. By degree of substitution is meant theaverage number of hydroxyl groups originally present on theanhydroglucose unit that are replaced by a substituting group, orconverted into another group. The anhydroglucose unit can be partiallyor completely substituted with groups such as acyl, alkanoyl, alkenoyl,aroyl, alkyl, alkoxy, halogen, carboalkyl, alkylcarbamate,alkylcarbonate, alkylsulfonate, alkylsulfamate, and semipermeablepolymer forming groups.

The semipermeable materials typically include a member selected from thegroup consisting of cellulose acylate, cellulose diacylate, cellulosetriacetate, cellulose acetate, cellulose diacetate, cellulosetriacetate, mono-, di-, and tri-cellulose alkanylates, mono-, di-, andtri-alkenylates, mono-, di-, and tri-aroylates, and the like. Exemplarypolymers including cellulose acetate having a D.S. of 1.8 to 2.3 and anacetyl content of 32 to 39.9%; cellulose diacetate having a D.S. of 1 to2 and an acetyl content of 21 to 35%; cellulose triacetate having a D.S.of 2 to 3 and an acetyl content of 34 to 44.8%; and the like. Morespecific cellulosic polymers include cellulose propionate having a D.S.of 1.8 and a propionyl content of 38.5%; cellulose acetate propionatehaving an acetyl content of 1.5 to 7% and an acetyl content of 39 to42%; cellulose acetate propionate having an acetyl content of 2.5 to 3%,an average propionyl content of 39.2 to 45% and a hydroxyl content of2.8 to 5.4%; cellulose acetate butyrate having a D.S. of 1.8, an acetylcontent of 13 to 15%, and a butyryl content of 34 to 39%; celluloseacette butyrate having an acetyl content of 2 to 29.5%, a butyrylcontent of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%; cellulosetriacylates having a D.S. of 2.9 to 3 such as cellulose trivalerate,cellulose trilaurate, cellulose tripalmitate, cellulose trioctanoate,and cellulose tripropionate; cellulose diesters having a D.S. of 2.2 to2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dicarpylate and the like; mixed cellulose esterssuch as cellulose acetate valerate, cellulose acetate succinate,cellulose propionate succinate, cellulose acetate octanotate, cellulosevalerate palmitate, cellulose acetate heptonate, and the like.Semipermeable polymers are known in U.S. Pat. No. 4,077,407, and theycan be made by procedures described in Encyclopedia of Polymer Scienceand Technology, Vol. 3, pages 325 to 354, 1964, published byInterscience Publishers, Inc., New York.

Additional semipermeable polymers include cellulose acetaldehydedimethyl acetate; cellulose acetate ethylcarbamate; cellulose acetatemethylcarbamate; cellulose dimethylaminoacetate; semipermeablepolyamides; semipermeable polyurethanes; semipermeable sulfonatedpolystyrenes; cross-linked, selectively semipermeable polymers formed bythe coprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006; and 3,546,142;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable polystyrene derivatives; semipermeablepoly(sodium styrenesulfonate); semipermeable poly(vinylbenzyltrimethyl)ammonium chloride; semipermeable polymers exhibiting a fluidpermeability of 10 to 10 (cc. mil/cm.hr.atm) expressed as per atmosphereof hydrostatic or osmotic pressure difference across a semipermeablewall. The polymers are known to the art in U.S. Pat. Nos. 3,845,770;3,916,899; 3,916,899; and 4,160,020, and in Handbook of Common Polymers,by Scott, J. R. and Roff, W. J., 1971, published by CRC Press,Cleveland, Ohio.

Drawing FIG. 3 illustrates another dosage form 10 provided by theinvention. In FIG. 3, dosage form 10 comprises a body 11, comprisingwall 12, orifice 13, that surrounds internal compartment 14. Internalcompartment 14 comprises a one-piece capsule 15. Capsule 15 comprises apharmaceutical emulsion formulation 19 comprising drug 20 and anexpandable composition 18. Capsule 15 is surrounded and/or coated bysemipermeable wall 12. The presentation of dosage form 10 in drawingFIG. 2 is referred to and included in this presentation of dosage form10 in drawing FIG. 3. The one-piece capsule used by the invention can bemade by different operations. The one-piece capsule is of a sealedconstruction encapsulating the drug and the emulsion formulationtherein. The capsule is made by various processes including the plateprocess, the rotary die process, the reciprocating die process, and thecontinuous process. The plate process uses a set of molds. A warm sheetof a prepared capsule lamina-forming material is laid over the lowermold and the formulation poured on it. A second sheet of thelamina-forming material is placed over the formulation followed by thetop mold. The mold set is placed under a press and a pressure applied,with or without heat to form a unit, capsule. The capsules are washedwith a solvent for removing excess agent formulation from the exteriorof the capsule, and the air-dried capsule is capsuled with asemipermeable wall.

The rotary die process uses two continuous films of capsulelamina-forming material that are brought into convergence between a pairof revolving dies and an injector wedge. The process fills and seals thecapsule in dual and coincident operations. In this process, the sheetsof capsule lamina-forming material are fed over guide rolls, and thendown between the wedge injector and the die rolls. The agent formulationto be capsuled flows by gravity into a positive displacement pump. Thepump meters the agent formulation through the wedge injector and intothe sheets between the die rolls. The bottom of the wedge contains smallorifices lined up with the die pockets of the die rolls. The capsule isabout half-sealed when the pressure of pumped agent formulation forcesthe sheets into the die pockets, wherein the capsules are simultaneouslyfilled, shaped, hermetically sealed and cut from the sheets oflamina-forming materials. The sealing of the capsule is achieved bymechanical pressure on the die rolls and by heating of the sheets oflamina-forming materials by the wedge. After manufacture, the agentformulation-filled capsules are dried in the presence of forced air, anda semipermeable lamina capsuled thereto, by processes describedhereafter.

The reciprocating die process produces capsules by leading two films ofcapsule lamina-forming material between a set of vertical dies. The diesas they close, open, and close perform as a continuous vertical plateforming row after row of pockets across the film. The pockets are filledwith agent formulation, and as the pockets move through the dies, theyare sealed, shaped, and cut from the moving film as capsules filled withagent formulation. A semipermeable capsulating lamina is coated thereonto yield the capsule. The continuous process is a manufacturing systemthat also uses rotary dies, with the added feature that the process cansuccessfully fill active agent in dry powder form into a soft capsule,in addition to encapsulating liquids. The filled capsule of thecontinuous process is encapsulated with a semipermeable polymericmaterial to yield the capsule. Drawing FIG. 3 shows the expandablecomposition which is an osmotic engine and the emulsion formulation inthe soft gelatin capsule. Procedures for manufacturing single-piececapsules are disclosed in U.S. Pat. No. 4,627,850, issued to inventorsDeters, Theeuwes, Mullins and Eckenhoff.

Drawing FIG. 4 illustrates another dosage form 10 provided by theinvention. In drawing FIG. 3, dosage form 10 comprises body 11, wall 12,orifice 13, made as capsule 15 comprising an internal emulsionformulation 19 comprising drug 20. Capsule 15 comprises an expandablecomposition 18. The presentation of the parts identified by numbers asdiscussed above is incorporated in the disclosure of drawing FIG. 4.

In drawing FIG. 4, dosage form 10, which is in this manufacture ofcapsule 15, is made from an injection-moldable composition by aninjection-molding technique. Injection-moldable compositions providedfor injection-molding into wall 12 comprise a thermoplastic polymer, orthe compositions comprise a mixture of thermoplastic polymers andoptional injection-molding ingredients. The thermoplastic polymer thatcan be used for the present purpose comprise polymers that have a lowsoftening point, for example, below 200° C., preferably within the rangeof 40° C. to 180° C. The polymers, are preferably synthetic resins,addition polymerized resins, such as polyamides, resins obtained fromdiepoxides and primary alkanolamines, resins of glycerine and phthalicanhydrides, polymethane, polyvinyl resins, polymer resins withend-positions free or esterified carboxyl or caboxamide groups, forexample with acrylic acid, acrylic amide, or acrylic acid esters,polycaprolactone, and its copolymers with dilactide, diglycolide,valerolactone and decalactone, a resin composition comprisingpolycaprolactone and polyalkylene oxide, and a resin compositioncomprising polycaprolactone, a polyalkylene oxide such as polyethyleneoxide, poly(cellulose) such as poly(hydroxypropylmethylcellulose),poly(hydroxyethylmethylcellulose), and poly(hydroxypropylcellulose). Themembrane forming composition can comprise optional membrane-formingingredients such as polyethylene glycol, talcum, polyvinylalcohol,lactose, or polyvinyl pyrrolidone. The compositions for forming aninjection-molding polymer composition can comprise 100% thermoplasticpolymer. The composition in another embodiment comprises 10% to 99% of athermoplastic polymer and 1% to 90% of a different polymer with thetotal equal to 100%. The invention provides also a thermoplastic polymercomposition comprising 1% to 98% of a first thermoplastic polymer, 1% to90% of a different, second polymer and 1% to 90% of a different, thirdpolymer with all polymers equal to 100%. Representation compositioncomprises 20% to 90% of thermoplastic polycaprolactone and 10% to 80% ofpoly(alkylene oxide); a composition comprising 20% to 90%polycaprolactone and 10% to 60% of poly(ethylene oxide) with theingredients equal to 100%; a composition comprising 10% to 97% ofpolycaprolactone, 10% to 97% poly(alkylene oxide), and 1% to 97% ofpoly(ethylene glycol) with all ingredients equal to 100%; a compositioncomprising 20% to 90% polycaprolactone and 10% to 80% ofpoly(hydroxypropylcellulose) with all ingredients equal to 100%; and acomposition comprising 1% to 90% polycaprolactone, 1% to 90%poly(ethylene oxide), 1% to 90% poly(hydroxypropylcellulose) and 1% to90% poly(ethylene glycol) with all ingredients equal to 100%. Thepercent, expressed is weight percent wt %.

In another embodiment of the invention, a composition forinjection-molding to provide a membrane is prepared by blending acomposition comprising a polycaprolactone 63 wt %, polyethylene oxide 27wt %, and polyethylene glycol 10 wt % in a conventional mixing machine,such as a Moriyama® Mixer at 65° C. to 95° C., with the ingredientsadded to the mixer in the following addition sequence, polycaprolactone,polyethylene oxide and polyethylene glycol. All the ingredients weremixed for 135 minutes at a rotor speed of 10 to 20 rpm. Next, the blendis fed to a Baker Perkins Kneader® extruder at 80° C. to 90° C., at apump speed of 10 rpm and a screw speed of 22 rpm, and then cooled to 10°C. to 12° C., to reach a uniform temperature. Then, the cooled extrudedcomposition is fed to an Albe Pelletizer, converted into pellets at 250°C., and a length of 5 mm. The pellets next are fed into aninjection-molding machine, an Arburg Allrounder® at 200° F. to 350° C.(93° C. to 177° C.), heated to a molten polymeric composition, and theliquid polymer composition forced into a mold cavity at high pressureamd speed until the mold is filled and the composition comprising thepolymers are solidified into a preselected shape. The parameters for theinjection-molding consists of a band temperature through zone 1 to zone5 of the barrel of 195° F. (91° C.) to 375° F., (191° C.), aninjection-molding pressure of 1818 bar, a speed of 55 cm³/s, and a moldtemperature of 75° C. The injection-molding compositions andinjection-molding procedures are disclosed in U.S. Pat. No. 5,614,578issued to Dong, Wong, Pollock, and Ferrari.

The expression as used herein comprises means and methods suitable forreleasing the useful, active drug emulsion formulation from the dosageform. The expression includes passageway, aperture, hole, bore, pore,and the like through the semipermeable wall. The orifice can be formedby mechanical drilling, laser drilling, or by eroding an erodibleelement, such as a gelatin plug, a pressed glucose plug, by crimping thewalls to yield the orifice when the dosage form is in the environment ofuse. In an embodiment, the orifice in wall 12 is formed in thenvironment of use in response to the hydrostatic pressure generated indosage form 10. The orifice 13 can be formed by mechanical rupturing ofwall 12 during operation of dosage form 10. A detailed description oforifices and the maximum and minimum dimensions of an orifice aredisclosed in U.S. Pat. Nos. 3,845,770 and 3,916,899, both issued toinventors Theeuwes and Higuchi.

EXAMPLES OF THE INVENTION

The following examples are illustrative of the present invention, andthe examples should not be considered as limiting the scope of thisinvention in any way, as these examples and other equivalents thereofwill become apparent to those versed in the art in the light of thepresent disclosure, and the accompanying claims.

Example 1

A dosage form is manufactured for dispensing a beneficial drug,progesterone, to the gastrointestinal tract of a human as follows:first, an expandable composition is prepared in a fluid bed granulator.The expandable composition comprises 30 wt % sodium chloride screenedthrough a 21 mesh screen, added to a granulator bowl, followed by 58.75wt % sodium carboxymethylcellulose, 5 wt % hydroxypropylmethylcellulose,and 1 wt % red ferric oxide added to the granulator bowl. In a separatemixer, a granulation solution is prepared by dissolving 5 wt %hydroxypropylcellulose in purified water. Next, the granulating solutionis sprayed onto the fluidized powders, in the granulated unit, until allthe solution is applied and the powders are granular. Next, 0.25 wt %magnesium stearate lubricant is blended with the freshly preparedgranules.

Next, the granules are compressed into a tablet-shaped layer comprising250 mg of the granules, in a {fraction (9/32)} inch punch, and tampedand then compressed under a force of 1 metric ton.

Next, a drug layer is prepared as follows: first, 50 wt % ofmicrofluidized progesterone, 12.5 wt % polyoxyl 35 castor oil, availableas Cremophor EL from BASF Corp., Mount Olive, N.J., and 37.5 wt %acetylated monoglyceride, commercially available as Myvacet from EastmanChemical Company, Kingsport, Tenn., are mixed homogenously in ahomogenizer.

Then, a capsule, made of gelatin, commercial size 0, is separated intoits two segments, the body and its cap. First, 600 mg of the drug layeris filled into the gelatin capsule body. Then, the expandable tablet isplaced on the top of the drug formulation, and the filled capsule bodyis closed with the gelatin cap.

The assembled capsule is coated with a semipermeable wall. Thewall-forming composition comprises 85 wt % cellulose acetate comprisinga 39.8% acetyl content, and 15 wt % polyethylene glycol 3350. Thewall-forming composition is dissolved in acetone/methanol (80/20 wt/wt)cosolvent to make a 4% solid solution. The solution is sprayed onto andaround the closed capsule in a coater. After coating, the semipermeablewall coated capsules are dried in an oven at 50° C. and 50° R.H.(relative humidity) for 1 day, to remove the solvents, and yield thedosage form. An exit is laser drilled through the wall. The dosage formreleases 90% of its progesterone in 12 hrs., at a controlled rate, whichis exemplified in FIG. 5A and FIG. 5B. The bars represent the minimumand maximum.

Example 2

The procedure of Example 1 is followed with all conditions as set forth,except the drug composition comprises 50 wt % progesterone, 37.5 wt %polyoxyl 35 castor oil, and 12.5 wt % distilled acetylatedmonoglyceride, commercially available as Myvacet from Eastman ChemicalCompany, Kingsport, Tenn.

Example 3

The procedure of Example 1 is followed with all conditions as set forth,except the drug composition comprises 50 wt % progesterone, 25 wt %polyoxyl 35 castor oil, and 25 wt % acetylated monoglyceride.

Example 4

The procedure of Example 1 is repeated with all conditions as previouslydescribed, except for the drug layer which comprises 50 wt %progesterone, and 50 wt % polyoxyl 35 castor oil.

The dosage form release rate profile for the dosage form preparedaccording to Examples 2 to 4 are illustrated in the accompanyingdrawing. Accompanying FIG. 6 depicts the progesterone release rate ofdosage forms with various sufactant/oil ratios. FIG. 7 is a phasediagram comprising three components, Cremophor EL polyoxyl 35 castoroil, Myvacet distilled acetylated monoglyceride, and water when theself-emulsifying formulation is mixed with water at 37° C. The phasediagram demonstrates that the liquid formulation can self-emulsify insitu to micelles, microemulsion and emulsions depending upon the ratioof the components in the phase diagram. FIG. 8 depicts the correlationbetween the ratio and the oil droplets size, is demonstrated by theself-emulsification to microemulsion by the polyoxyl 35 castoroil-distilled acetylated monoglyceride ratio higher than 50/50. In FIG.8, the following conditions prevailed: Pre-mixed Cremophor EL/Myvacetwas added to water, and stirred. Particle size was measured using asub-micro particle size analyzer. Sample intensity was in the requiredrange.

Cremophor EL/Myvacet Particle Size, nm SD # of Run 75/25 16 1 2 50/50 8423 3 25/75 198 5 6

In the chart, SD denotes standard deviation and # denotes the number ofruns. FIG. 9 is the solubility profile of progesterone in the polyoxyl35 castor oil and distilled acetylated monoglycerides at various weightratios. FIG. 10 shows the enhancement of progesterone solubility inwaterby using liquid carrier, wherein comprising polyoxyl 35 castor oiland distilled acetylated monoglyceride.

Example 5

Pharmacokinetic studies were conducted using the dosage form provided bythe invention. In this study, dosage forms were administered to canines,wherein the dosage forms comprises 1 g of liquid emulsion formulationcontaining 40 mg of progesterone. The AUC, area under the curve, asdetermined by trapezoidal rule from time zero to the last blood samplingpoint, which is the 12^(th) hour. The AUC of the dosage form comprisespolyoxyl 35 castor oil, and distilled acetylated monoglyceride was 226ng/ml-h compared to 104 ng/ml-h for the control. The mean C max for thedosage form was 197 ng/ml compared to 25.6 ng/ml for the control. Thecontrol was a solid dosage form comprising progesterone in a nonemulsionformulation (#1 formulation). A suspension of 300 mg progesterone inpolyoxyl 35 castor oil/distillated acetylated monoglyceride liquidcarrier was tested in the study. The results for the liquid carrier ofthe invention showed a C max of 4467 ng/ml compared to 639 ng/ml for thecontrol. The bioavailability of the dosage form of the invention isabout 600% relative to the control. In a previous clinical study, thecontrol formulation showed a bioavailability of 83% relative to acommercial product, Utrogestrin®. The present canine pharmacokineticstudy demonstrated the dosage form of this invention with unexpectedresults and microemulsion formulation of the invention is very effectiveto enhance the bioavailability of water-insoluble drugs. The results ofthe study are presented in the accompanying Figures, wherein in FIG. 11,the control denotes a solid dosage form comprising progesterone in anonemulsion environment; Pro/CremEL/Myva denotes progesterone in apolyoxyl 35 castor oil/distilled acetylated monoglyceride emulsion;wherein (50/25/25) denotes the ratio in the composition,progesterone/Cremophor denotes progesterone formulated with polyoxyl 35castor oil; progesterone/Myvacet denotes progesterone in distilledacetylated monoglyceride; and Pro/CremEL/Olive Oil denotes progesteroneformulated with polyoxyl 35 castor oil/olive oil; drawing FIG. 12depicts canine studies in six canines for determining the serumprogesterone concentration comparing solid control formulation withemulsion formulation where closed symbols represent solid dosage formseach delivering 40 mg of progesterone, and open symbols represent theliquid carrier provided by the invention wherein the carrier comprises40 mg of progesterone in an emulsion formulation; drawing FIG. 13depicts the serum concentration comparing the solid control dosage formswith emulsion formulation where closed symbols represent the soliddosage form each delivering 300 mg of progesterone and open symbolsrepresent the emulsion formulation provided by this invention, whereinthe emulsion formulation comprise 300 mg of progesterone; drawing FIG.14 depicts the pharmacokinetic results for oral preparations (40 mg)provided by the invention; and drawing FIG. 15 depicts thepharmacokinetic data for a large 300 mg study.

METHOD OF USING THE INVENTION

The invention provides a method of administering a drug by orallyadmitting into the gastrointestinal tract of a human the dosage form ofthe invention. The method comprises the steps of (1) admitting orallythe dosage form into the gastrointestinal tract; which dosage formcomprises a wall for imbibing an external aqueous fluid through the wallinto the dosage form and surrounds and forms a space comprising agelatin capsule comprising an emulsifiable formulation comprising adrug, and a push-up displacement composition; (2) permitting the aqueousfluid to dissolve the gelatin capsule in the dosage form; (3) lettingimbibed fluid mix with the emulsifiable formulation to form adispensable emulsion; and (4) letting imbibed fluid cause thepush-displacement layer to expand and push the emulsified formulationthrough an orifice at a controlled rate over a sustained release periodup to 24 hrs. for therapy.

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is understood that variations and modifications maybe made herein, in accordance with the inventive principles disclosed,without departing from the scope of the invention.

What is claimed is:
 1. A process for providing a sustained-release,liquid formulation dosage form, wherein the process comprises the stepsas follows: (a) blending an osmotic hydrogel and an osmoticallyeffective solute to provide a composition that increases in volume inthe presence of an aqueous fluid; (b) blending a hydroxyalkylcelluloseand water to provide a granulation solution; (c) spraying thegranulation solution of step (b) onto the composition provided in step(a) to provide granules; (d) forming a blended, liquid mixtureconsisting essentially of a drug, a surfactant, and a member selectedfrom the group consisting of a mono- and di-glyceride to provide a drugformulation that is liquid upon administration and is adapted toself-emulsify in an aqueous environment; (e) adding the drug formulationformed in step (d) to a capsule; (f) adding the sprayed composition ofstep (c) to the capsule; (g) coating the capsule with a semipermeablecomposition to provide a membrane permeable to an aqueous fluid; and (h)providing an exit in the membrane formed in step (g) for delivering thedrug formulation at a sustained-release and controlled rate over anextended time from the dosage form and providing a self-emulsifying drugformulation to the environment of use.
 2. The process for providing thedosage form according to claim 1, wherein step (b) precedes step (a). 3.The process for providing the dosage form according to claim 1, whereinstep (f) precedes step (e).
 4. The process for providing the dosage formaccording to claim 1, wherein the membrane formed in step (g) comprisesa cellulose acetate and polyethylene glycol.
 5. The process forproviding the dosage form according to claim 1, wherein the surfactantpolyoxyl 35 castor oil an the monoglyceride is acetylated monoglyceride.6. The process for providing the dosage form according to claim 1,wherein the drug of step (d) selected from the group consisting of apeptide, protein, protein anabolic hormone, growth promoting hormone,endocrine system hormone, procine growth hormone, bovine growthpromoting hormone, equine growth promoting hormone, human growthpromoting hormone, hormones derived from pituitary gland, hormonederived from a hypothalmus gland, recombinant DNA, samatotropin,gonadotropic releasing hormone, follicle stimulating hormone,luteinizing hormone, LH-RH, insulin, colchicine, chlorionicgonadotropin, oxytocin, vasopressin, desmopressin, adrenocorticotrophichormone, prolactin, bypressin, thyroid stimulating hormone, secretin,pancreozymin, enkephalin, and glucagon.
 7. The process for providing thedosage form according to claim 1, wherein the membrane formed in step(g) comprises injection moldable composition thermoplastic polymercomposition possessing a softening point of 40° C. to 180° C.
 8. Theprocess for providing the dosage form according to claim 1, wherein thedrug formulation of step (d) comprises a two-phase emulsion andcomprises an agent that imparts emulsification to the drug formulationis selected from the group consisting of polyoxyethylenated castor oilcomprising 9 to 52 moles of ethylene oxide, polyoxyethylenated sorbitanmonopalmitate comprising 20 of ethylene oxide, polyoxyethylenatedsorbitan monostearate comprising 20 mules of ethylene oxide,polyoxyethylenated sorbitan monostearate comprising 4 moles of ethyleneoxide, polyoxyethylenated sorbitan tristearate comprising 20 moles ofethylene oxide, polyoxyethylenated sorbitan monostearate comprising 20moles of ethylene oxide, polyoxyethylenated sorbitan trioleatecomprising 20 moles of ethylene oxide, polyoxyethylene stearic acidcomprising 8 moles of ethylene oxide, polyoxyethylene lauryl ether,polyoxyethylenated stearic acid comprising 40 moles to 50 moles ofethylene oxide, polyoxyethylenated stearic acid comprising 50 moles ofethylene oxide, polyoxyethylenated stearyl alcohol comprising 2 moles ofethylene oxide, and polyoxyethylenated oleyl alcohol comprising 2 molesof ethylene oxide.